Although asthma is likely to be a heterogenous disease or syndrome, three factors and/or events repetitively emerge for their ability to significantly influence asthma inception in the first decade of life: immune response aberrations, which appear to be defined best by the concept of cytokine dysregulation; lower respiratory tract infections (in particular RSV); and some form of gene by environment interaction that needs to occur at a critical time period in the development of the immune system or the lung. It remains to be firmly established, however, how any one or all of these factors, either independently or interactively, influence the development of childhood asthma. For example, cytokine dysregulation (Th1/Th2 imbalance) appears to track best epidemiologically with allergic diseases. Since not everyone who undergoes allergic sensitization develops asthma, some other host/environment interaction must need to occur to target this chronic allergic inflammatory response to the lower airway. Some evidence suggests that this event might be an environmental insult in the form of a virus infection, particularly with respiratory syncytial virus (RSV), which has a predilection for infecting, destroying, and or in some way biologically altering lower airway epithelium. However, only a fraction of children develop recurrent wheezing following RSV infections despite the fact that nearly all children have been infected at least once by the age of 2 years. Thus, although RSV infections may have the potential of targeting the inflammatory response to the lower airway, they may only be able to do so during a vulnerable time period in immune system or lung development. This developmental component may further reflect important gene-by-environment interactions that regulate both short- and long-term airway physiologic alterations that manifest themselves clinically as childhood asthma. This grant application will use an established cohort of infants and children at high risk of developing allergies and/or asthma to prospectively evaluate how these three variables influence the pathogenesis of asthma from the standpoints of both inception and exacerbation. The specific aims are structured to evaluate the inception, progression, and/or regression of various wheezing/asthmatic and allergic phenotypes. They will be multidisciplinary with the involvement of immunologic, microbiologic, physiologic, epidemiologic, and genetic studies to comprehensively address these research questions, which appear to be fundamental to the development of improved recognition and treatment strategies for childhood asthma.